PRIMARY OBJECTIVES:
I. To determine the efficacy measured by complete remission (CR) rate of the acalabrutinib in
combination with rituximab in newly diagnosed elderly mantle cell lymphoma (MCL) patients.
II. To determine the safety profile of acalabrutinib with rituximab combination in elderly
patients with MCL.
SECONDARY OBJECTIVES:
I. To evaluate the overall response (OR) rate. II. To evaluate the progression-free survival
and overall survival. III. To assess serial minimal residual disease (MRD) using clonoseq,
circulating tumor deoxyribonucleic acid (ct-DNA) based serial clonal evolution.
IV. Perform baseline genomic profiling for recognizing the predictive signature for response,
serial MCL specific analytes assessments while on therapy.
EXPLORATORY OBJECTIVES:
I. Clonal evolution with targeted sequencing (seq) on ctDNA samples in sequential samples
using a MCL specific customized gene panel would be assessed.
II. MRD assay using IgH clonoseq and ctDNA analysis, flow cytometry at various time points
from peripheral blood (PB)/bone marrow (BM).
III. Sequential immunologic studies with cytokines/chemokines using a analyte panel, T cell
numbers, and immunoglobulins (Ig).
IV. Tissue microenvironmental studies with simultaneous assessment of PB, BM and lymph nodes
for gene expression profiling (GEP), single cell seq, ribonucleic acid (RNA) seq and clonal
heterogeneity and the impact of acalabrutinib (A)-rituximab (R) treatment.
V. Extensive bioinformatics studies. VI. Identification of signaling pathways or biomarkers
that predict sensitivity after therapy.
OUTLINE:
Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Cycles repeat
every 28 days in the absence of disease progression or unacceptable toxicity. Patients also
receive rituximab intravenously (IV) over 3-4 hours on days 1, 8, 15, and 22 of cycle 1, and
day 1 of cycles 2-12, 14, 16, 18, 20, and 24. Cycles repeats every 28 days for up to 24
months or until complete remission is achieved in the absence of disease progression or
unacceptable toxicity.
After completion of study intervention, patients are followed up at 30 days, every 4 months
for 2 years, every 6 months for 2 years, and then annually for 3 years.
Inclusion Criteria:
- Pathology confirmed diagnosis of mantle cell lymphoma with CD20 positivity and
chromosome translocation t (11;14), (q13;q32) and/or positive cyclin D1 in tissue
biopsy
- Newly diagnosed elderly MCL (age >= 65 years) with no prior therapy under all risk
categories
- Patients with preexisting well-controlled cardio-vascular comorbidities - patients on
anticoagulants (excluding warfarin and vitamin K antagonists), antiplatelet,
anti-hypertensive, prior ablation, anti-arrhythmia, prior arrhythmias, baseline
electrocardiogram (EKG) abnormalities and cardiology clearance are allowed. Ejection
fraction >= 50% and cardiology clearance are required
- Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed
consent form
- Bi-dimensional measurable disease using the Cheson criteria (measurable disease by
positron emission tomography [PET]-computed tomography [CT] scan defined as at least 1
lesion that measures >= 1.5 cm in single dimension.) Gastrointestinal, bone marrow or
spleen only patients are allowable
- Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
- Absolute neutrophil count (ANC) >= 1,000/mm^3 (Patients who have bone marrow and
spleen infiltration by MCL are eligible, the ANC and platelets counts will not be
limited)
- Platelet count >= 100,000/mm^3 (Patients who have bone marrow and spleen infiltration
by MCL are eligible, the ANC and platelets counts will not be limited)
- Serum bilirubin =< 1.5 mg/dl
- Creatinine clearance minimum to 50 mL/min per the Cockcroft-Gault formula
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2 x
upper limit of normal or =< 5 x upper limit of normal if hepatic metastases are
present. Gilbert's disease is allowed
- Disease free of prior malignancies with exception of currently treated basal cell,
squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or
other malignancies in remission (including prostate cancer patients in remission from
radiation therapy, surgery or brachytherapy), not actively being treated with life
expectancy of > 3 years. Principal investigator (PI) can use clinical judgement in the
best interest of patients
- Women of childbearing potential (WOBP) must have a negative serum or urine pregnancy
test. WOBP and males must be willing to use highly effective methods of birth control.
therapy. Woman of childbearing potential (WOCBP) who are sexually active must use
highly effective methods of contraception during treatment and for 2 days after the
last dose of acalabrutinib and for 12 months following the last dose of rituximab. For
male subjects with a pregnant or non-pregnant WOCBP partner, should use barrier
contraception, during treatment and for 2 days after the last dose of acalabrutinib
and for 1 month following the last dose of rituximab even if they have had a
successful vasectomy
Exclusion Criteria:
- Patients with central nervous system involvement with mantle cell lymphoma or with
suspected or confirmed progressive multifocal leukoencephalopathy (PML) are excluded
since those patients have very poor prognosis, need aggressive intensive
chemoimmunotherapy and intrathecal chemotherapy along with Bruton's tyrosine kinase
(BTK) inhibitors and these patients would not be eligible for this study
- Pregnant or breast-feeding females
- Has difficulty with or is unable to swallow oral medication, or has significant
gastrointestinal disease that would limit absorption of oral medication
- Known history of hypersensitivity or anaphylaxis to study drug(s) including active
product or excipient components
- Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin
time (aPTT) (in the absence of lupus anticoagulant) > 2 x upper limit of normal (ULN)
- Concurrent participation in another therapeutic clinical trial
- Immunization with live vaccine within 4 weeks of and during therapy with rituximab
- Subjects who are hepatitis B or C polymerase chain reaction (PCR) positive. Those with
prior hepatitis B (Hep-B) vaccination (i.e., hepatitis B surface antibody [anti-HBs]
antibody positive) or natural immunity as evidenced by the presence of anti-HBs and
hepatitis B core antibody (anti-HBc) positivity are eligible to enroll. (Known
hepatitis C infection is allowed as long as there is no active disease and is cleared
by gastrointestinal [GI] consultation)
- Patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome
(AIDS)
- Active bleeding, history of bleeding diathesis (such as Hemophilia or Von-Willbrand
disease), any history of intracranial bleed or stroke within 6 months of first dose of
study drug
- Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
purpura)
- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel or ulcerative colitis, symptomatic
inflammatory bowel disease, or partial or complete bowel obstruction, or any other
gastrointestinal condition that could interfere with the absorption and metabolism of
acalabrutinib
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
first dose of study drug
- Major surgery within 4 weeks of initiation of therapy
- Requires anticoagulation with warfarin or equivalent vitamin K antagonist
- Concomitant use of corticosteroids at > 20 mg prednisone or equivalent per day > 2
weeks
- Requires treatment with strong CYP3A inhibitors or inducers
- Patients who have had a stroke within 6 months
- Any of the following conditions considered clinically significant cardiovascular
diseases as determined after cardiology consultation:
- Diagnosed congestive heart failure
- Active/symptomatic coronary artery disease
- Congestive heart failure
- Myocardial infarction in the preceding 6 months
- Significant conduction abnormalities, including but not limited to:
- Left bundle branch block
- 2nd degree atrioventricular (AV) block type II
- 3rd degree block
- QT prolongation (corrected QT [QTc] > 480 msec)
- Sick sinus syndrome
- Ventricular tachycardia
- Symptomatic bradycardia (heart rate < 50 bpm)
- Persistent, controlled and uncontrolled atrial fibrillation
- Uncontrolled hypertension
- Hypotension
- Light headedness and syncope
- Active infection
- Acute infection requiring systemic anti-microbial treatment (systemic antibiotics,
antivirals, or antifungals) within 14 days prior to initiation of therapy
- Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole or pantoprazole). Subjects receiving
proton-pump inhibitors who switch to H2-receptor antagonists (2 hours after
acalabrutinib/placebo) or antacid (2 hours before or 2 hours after
acalabrutinib/placebo). Avoid co-administration with proton pump inhibitors
- Active infection including systemic fungal or cytomegalovirus (CMV) infection who were
hospitalized in past 6 months
- Any other serious medical condition including, but not limited to, uncontrolled
diabetes mellitus, uncontrolled thyroid disorder, uncontrolled hypertension (i.e.
uncontrolled blood pressure [BP] - > 160/110 in spite of 3 different classes of full
dose anti-hypertensives medications and in spite of cardiology evaluation;
documentation from cardiology is required to say that the BP is uncontrollable),
chronic obstructive pulmonary disease (COPD), renal failure, psychiatric illness or
social circumstances that, in the investigator's opinion places the patient at
unacceptable risk and would prevent the subject from signing the informed consent form
or complying with study procedures
